The loss of GLUT2 expression in the pancreatic beta-cells of diabetic db/db mice is associated with an impaired DNA-binding activity of islet-specific trans-acting factors.
GLUT2 expression is reduced in the pancreatic beta-cells of several diabetic animals. The transcriptional control of the gene in beta-cells involves at least two islet-specific DNA-binding proteins, GTIIa and PDX-1, which also transactivates the insulin, somatostatin and glucokinase genes. In this report, we assessed the DNA-binding activities of GTIIa and PDX-1 to their respective cis-elements of the GLUT2 promoter using nuclear extracts prepared from pancreatic islets of 12 week old db/db diabetic mice. We show that the decreased GLUT2 mRNA expression correlates with a decrease of the GTIIa DNA-binding activity, whereas the PDX-1 binding activity is increased. In these diabetic animals, insulin mRNA expression remains normal. The adjunction of dexamethasone to isolated pancreatic islets, a treatment previously shown to decrease PDX-1 expression in the insulin-secreting HIT-T15 cells, has no effect on the GTIIa and PDX-1 DNA-binding activities. These data suggest that the decreased activity of GTIIa, in contrast to PDX-1, may be a major initial step in the development of the beta-cell dysfunction in this model of diabetes.
Bonny
C
C
Department of Internal Medicine B/19-135, University Hospital, CHUV, Lausanne, Switzerland.
Roduit
R
R
Gremlich
S
S
Nicod
P
P
Thorens
B
B
Waeber
G
G
D000818:Animals; D004247:DNA / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D015870:Gene Expression; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000378:metabolism*
D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D004247:DNA